This proposal describes a 5-year training program designed to develop an academic career for the candidate in vascular biology. The research focuses on vascular smooth muscle cell (VSMC) differentiation and phenotypic modulation with emphasis on the role of cell signaling in these processes. The activities proposed rely on a collaborative program of study under co-supervision of two internationally recognized principal investigators, Drs. Michael S. Parmacek, an expert in transcriptional regulation of VSMCs, and Warren S. Pear, a leader in the field of Notch signaling. Together, the candidate will utilize both intellectual and proprietary resources from these laboratories with further guidance by an advisory committee of distinguished physicians and scientists. Participation in didactic courses and research seminars will enhance the educational success of the program. The research plan centers on a role for Notch signaling in the differentiation and function of VSMCs. These cells have the unique capacity to alter their phenotype from contractile to proliferative activity in response to vascular injury and in the setting of vasculoproliferative disorders. Notch signaling is a well-described modulator of cell differentiation, proliferation and apoptosis, and animals deficient in select Notch signaling components display disrupted vascular development and homeostasis. Preliminary studies reveal that Notch signaling modulates VSMC-specific gene expression leading to the hypothesis that Notch signaling has an important role in the phenotypic regulation of VSMCs. Accordingly, specific aims of this proposal are to (1) determine the molecular basis of Notch signaling-induced smooth muscle gene expression; (2) determine the impact of dysregulated Notch signaling in established SMC differentiation systems and in mature VSMCs; and (3) determine the effect of inhibiting SMC-specific, RBP-Jk-dependent Notch signaling in mice. The Molecular Cardiology Research Center and the Abramson Cancer Center of the University of Pennsylvania provide extensive resources, collaborations, core facilities and intellectual expertise. As such, this is an ideal setting for the candidate to acquire mentored training towards an independent career as a physician-scientist. (End of Abstract)